A key feature of the central nervous system (“CNS”) is that differentiated neurons are essentially incapable of regeneration. Permanent loss of function is thus a likely outcome of a sufficiently severe injury or insult to the brain. Accordingly, there is a need for means to protect cells of the central nervous system from death after an injury. Damage to different cell types in the central nervous system, such as, asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischemic or hypoxic insults, may cause sensory, motor or cognitive deficits.
MicroRNAs (miRNAs) are single-stranded RNA molecules of about 21-23 nucleotides. A miRNA is complementary to the 3′ untranslated region (3′-UTR) of one or more messenger RNAs (mRNAs). The annealing of the miRNA to the mRNA causes inhibition of protein translation and/or facilitation of mRNA degradation. Recent studies reveal that miRNAs may play a key role in the process of atherosclerosis by influencing genetic expressions within vascular smooth muscle cells (VSMCs) and endothelial cells (Y. Suarez et al., Proc. Natl. Acad. Sci. USA 105, 14082, 2008; L. Poliseno et al., Blood 108, 3068, 2006; and X. Liu et al., Circ. Res. 104, 476 2009). For example, miR-145 was found to be a VSMC phenotypic marker and regulate vascular neointimal lesion formation (Y Cheng et al., Circ. Res. 105, 158, 2009). Elevated plasma levels of several miRNAs were also demonstrated in patients of acute myocardial infarction, suggesting that circulating miRNAs may serve as biomarkers of cardiovascular diseases (Y. D'Alessandra et al., Eur. Heart J. 31, 2765, 2010). However, miRNA studies in the context of atherosclerosis are still in the infantile stage.
Xu T et al. indicated that microRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells (Xu T et al., Hepatology. 2009 July; 50(1): 113-21). Huaqing Zhu et al. reported that microRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1 (Xu T et al., Cardiovasc Res (2011) first published online May 27, 2011). Sekiya Y et al. reported down-regulation of cyclin E1 expression by microrna-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation (Sekiya Y et al., J. Cell. Physiol. Vol. 226, No. 10, pp. 2535-2542, 2011).
U.S. patent application Ser. No. 12/635,178, filed on 10 Dec. 2009 discloses that microRNA-195 can be used in the treatment of atherosclerosis. Several risk factors can increase a risk for stroke. By reducing these risk factors can prevent stroke. Drug Discovery Today, Volume 17, Numbers 7/8, April 2012, pp. 296-309 states the prevention approaches of stroke. However, the reference also indicates that there are only few effective treatments for acute stroke (see page 299). Those of ordinary skill in the art know the prevention of stroke is not equal to treatment of acute stroke. Additional information for stroke treatment can be found in the website of National Stroke Association (http://www.stroke.org/site/PageServer?pagename=treatment). Therefore, the discovery of miR-195's effect on anti-atherosclerosis can not be extrapolated mir-195's therapeutic effect on acute stroke.
Kandiah Jeyaseelan et al. report that the involvement of miRNA regulation in brain pathogenesis associated with middle cerebral artery occlusion (MCAo) and indicate that comparison with the corresponding DNA microarray data revealed that the target mRNA expression is correlated with the regulation of miRNA (Kandiah Jeyaseelan et al., Stroke, March 2008, pp. 959-966). The reference also reports that some of the miRNAs that are highly expressed in the ischemic brain can be detected in blood samples; for example, microRNA-195 was found at 48-hour reperfusion in both the blood and brain samples. However, microRNA-195 showed an opposite trend in expression. Therefore, even persons skilled in the art would not be able to predict whether microRNA-195 can be neuroprotective or not after ischemic stroke.
Given the above, no prior references teach or suggest the neuroprotection effect caused by increasing an amount of a microRNA-195.